In:
PLOS Genetics, Public Library of Science (PLoS), Vol. 17, No. 7 ( 2021-7-27), p. e1009684-
Abstract:
Functional mechanisms remain unknown for most genetic loci associated to complex human traits and diseases. In this study, we first mapped trans -eQTLs in a data set of primary monocytes stimulated with LPS, and discovered that a risk variant for autoimmune disease, rs17622517 in an intron of C5ORF56 , affects the expression of the transcription factor IRF1 20 kb away. The cis-regulatory effect specific to IRF1 is active under early immune stimulus, with a large number of trans -eQTL effects across the genome under late LPS response. Using CRISPRi silencing, we showed that perturbation of the SNP locus downregulates IRF1 and causes widespread transcriptional effects. Genome editing by CRISPR had suggestive recapitulation of the LPS-specific trans -eQTL signal and lent support for the rs17622517 site being functional. Our results suggest that this common genetic variant affects inter-individual response to immune stimuli via regulation of IRF1 . For this autoimmune GWAS locus, our work provides evidence of the functional variant, demonstrates a condition-specific enhancer effect, identifies IRF1 as the likely causal gene in cis , and indicates that overactivation of the downstream immune-related pathway may be the cellular mechanism increasing disease risk. This work not only provides rare experimental validation of a master-regulatory trans -eQTL, but also demonstrates the power of eQTL mapping to build mechanistic hypotheses amenable for experimental follow-up using the CRISPR toolkit.
Type of Medium:
Online Resource
ISSN:
1553-7404
DOI:
10.1371/journal.pgen.1009684
DOI:
10.1371/journal.pgen.1009684.g001
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10.1371/journal.pgen.1009684.g002
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10.1371/journal.pgen.1009684.g003
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10.1371/journal.pgen.1009684.g004
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10.1371/journal.pgen.1009684.s001
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10.1371/journal.pgen.1009684.s022
DOI:
10.1371/journal.pgen.1009684.r001
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10.1371/journal.pgen.1009684.r002
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10.1371/journal.pgen.1009684.r003
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10.1371/journal.pgen.1009684.r004
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10.1371/journal.pgen.1009684.r005
DOI:
10.1371/journal.pgen.1009684.r006
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2186725-2
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